TEMPO‐Mediated Electrochemical N‐demethylation of Opiate Alkaloids

Abstract

A new TEMPO-mediated electrochemical method has been developed for N-demethylation of opiates using a home-made batch cell with low-cost porous glassy carbon electrodes. Ndemethylation of opiates such as thebaine, codeine, morphine and oxycodone is a key step in the semi-synthesis of opioid medicines. The electrochemical N-demethylation using TEMPO as mediator enables the synthesis of noropiates, which is not possible with conventional Shono oxidation. Electrolysis was performed at a preparative scale in aqueous solvent at room temperature in a single step, yielding the desired products in good isolated yields (up to 83 %). Mechanistic studies suggest that the electrochemically generated oxoammonium species oxidizes the opiate to an iminium intermediate, which then hydrolyzes to the noropiate. The electrochemical reaction was also performed in a flow-cell without a supporting electrolyte and represents the first electrochemical N-demethylation of difficult opiates with an aminoxyl oxidant.

N-Dealkylation of Amines

“…A low-cost DC-to-DC electrical converter connected to a solar-powered battery was used to replace the potentiostat by performing gram-scale synthesis of 27c using this system. Divided-cell electrochemical experiments and subsequent LC-MS analysis of anodic and cathodic compartment solutions showed that the reaction only occurs in the anodic cell, supporting the formation of an iminium intermediate as mentioned earlier [ 12 ] ( Figure 17 B). Frazier et al [ 154 ] patented an electrolytic process for glyphosate 90 production.…”

“…Naloxone 8 is an opiate antagonist listed on the Model List of Essential Medicines established by the World Health Organization and is used in life-threatening situations arising from synthetic or natural opiate overdose. Nalbuphine 9 is a mixed opiate agonist-antagonist which is used as analgesic to avoid undesirable effects of morphine [ 11 , 12 ]. The chemical structures of various semi-synthesized opioid medicines are given in Figure 1 (blue box).…”

“…After N -demethylation of the tertiary amine, the synthesized noropiates are functionalized with appropriate chemical groups to obtain specific therapeutic properties. A typical route for the synthesis of opioid medicines is the conversion of natural opiates 3 – 4 to oxycodone 10a or oxymorphone 11a followed by N -demethylation to noroxycodone 10b or noroxymorphone 11b and subsequent re-alkylation [ 12 , 13 , 14 ]. Therefore, different organic chemistry methods were developed for the selective N -demethylation of opiate alkaloids over a period of one century.…”

“…We recently showed that a TEMPO-mediated electrochemical strategy affords the N -demethylation of opiate alkaloids in one step [ 12 ]. This reaction proceeds in 70% aq.…”

Nanoporous Gold Catalyst for the Oxidative N‐Dealkylation of Drug Molecules: A Method for Synthesis of N‐Dealkylated Metabolites

“…Beside the importance of the N-dealkylation reaction in the synthesis of drug metabolites, this reaction provides important intermediates for the semi-synthesis of different medicines. [39,40] For example, N-dealkylation of atropine to noratropine is an important step for the semi-synthesis of the bronchodilator ipratropium bromide which is registered in WHO's list of essential medicines. [41,42] Oxidative catalytic N-demethylation of atropine 9 a in the presence of air as oxidant only led to 15 % conversion to 9 b, while using TBHP as oxidant led to 57 % isolated yield.…”